Glioblastoma multiforme (GBM), grade IV glioma, is the most malignant primary brain tumor, with a very poor prognosis (Stupp et al., 2005); the median survival is around 12 months, despite combined multimodal therapy (Dehdashti et al., 2006; Stupp et al., 2007; Stupp et al., 2005). To improve patient survival, the mechanisms of GBM's tumorigenesis need to be elucidated. Some studies have suggested that subsets of cancer stem cells (CSC) are key contributors to radioresistance and responsible for tumor progression as well as recurrence after conventional therapy (Bao et al., 2006). However, there is lack of suitable markers for isolating the crucial subset of tumor cells that is capable of reforming new tumors in vivo and accounts for tumor relapse in malignant glioma, according to CSC hypothesis of tumorigenesis (Chen et al., 2010).
MicroRNAs (miRNAs)—highly conserved small RNA molecules that regulate gene expression—can act as cancer signatures, oncogenes or tumor suppressors (Croce, 2009). MiRNAs appear to target oncogenes, cell cycle regulators and transcription factors, and regulate brain tumor progression (Gillies and Lorimer, 2007). In brain tumors, multiple miRNAs, including miR7, miR21, miR26a, miR124, miR137, miR184, and miRNA 221/222 have been implicated in GBM pathogenesis (Chan et al., 2005; Chen et al., 2008; Diehn et al., 2009; Huse et al., 2009; Kefas et al., 2008; Li et al., 2009; Malzkorn et al., 2009). Several miRNAs appear to be prognostic markers, such as miR10b and miR26a in high-grade glioma (Huse et al., 2009; Sasayama et al., 2009). MiRNAs are involved in many aspects of brain tumor progression, including glioma malignant progression. MiR125b, miR326, and miR324-5p—signature miRNAs in cerebellar neuronal progenitors and tumors—can help predict prognosis and patient outcome (Ferretti et al., 2008). Further, miR34 overexpression impairs the self-renewal properties of brain tumor and pancreatic cancer stem cells (CSCs) (Ji et al., 2009b). Recently, miR145 was found to modulate embryonic stem cell differentiation; this single miRNA simultaneously regulated multiple stemness genes, including KLF4, Oct4, and Sox2 (Xu et al., 2009). However, whether there is such a role for miRNAs in GBM relapse and secondary GBM that is mediated by regulation of stemness, tumor-initiating capability or mesenchymal transformation is unclear.
Mir142 was first reported to regulate hematopoiesis and T cell development (Chen et al., 2004). MiR142-3p expression is controlled by LMO2 binding to the putative promoter region of the miR142 gene (Yuan et al., 2008). The miR142 gene resides at the junction of the t(8;17) translocation, which appears to be associated with indolent lymphoma progression to aggressive B-cell leukemia due to strong upregulation of c-Myc (Gauwerky et al., 1989). Qian et al. (2008) found miR142-3p and miR142-5p upregulation in bronchioalveolar stem cells (BASCs) in mouse lung; aberrant miR142 expression could be involved in converting BASCs into lung cancer stem cells. Recently, Sun et al. (Sun et al., 2010) showed that miR-142 attenuates hematopoietic cell proliferation regulated by the miR-223-CEBP-β-LMO2 axis. CSCs isolated from glioma or GBM had elevated expression of stemness genes such as Sox2 (Gangemi et al., 2009). Sox2, a high-mobility-group DNA binding protein, is a critical marker of neural stem cells and has a key role in maintaining their undifferentiated state. Likewise, Sox2 expression has been proposed to be a signature of glioma and medulloblastoma and maintains CSC stemness (Decarvalho et al.; Sutter et al.). Importantly, gliosarcoma stem cells have high Sox2 expression, and Sox-2 knockdown further suppressed tumorigenicity and stemness in glioma CSCs (Decarvalho et al.).